Transgenerational inheritance of diabetes susceptibility in male offspring with maternal hyperandrogenism [WGBS]

Maternal hyperandrogenism is closely related to metabolic disorders, yet its transgenerational effects on male descendants remain unclear. Here we demonstrate that hyperandrogenism in women predisposes their sons to islet ß-cell dysfunction. Male offspring mice with prenatal androgen exposure exhibited hyperglycemia and glucose intolerance due to compromised insulin secretion. Notably, these metabolic disturbances were transmitted across three generations, and exacerbated by aging and a high-fat diet. Altered DNA methylations in F1 sperm and F2 islet contribute to suppressed ß-cell functional genes. We identified shared differentially methylated signatures in F1 sperm, type 2 diabetes patients, and sons with maternal hyperandrogenism. Furthermore, caloric restriction and metformin treatments in F1 males corrected hyperglycemic defects and prevented their transmission to offspring. Our findings highlight the transgenerational inheritance of hyperglycemia and ß-cell dysfunction in male offspring from maternal hyperandrogenism via DNA methylation changes, providing methylation biomarkers and therapeutic strategies to safeguard future generations' metabolic health. Overall design: To investigate the effect of prenatal androgen exposure on offspring metabolism, we sequenced sperm from first-generation male mice